Molecular Pharmacology, Vol 16, 369-381, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

The Conformation of Dopamine at Its Receptor: Binding of Monohydroxy-2-aminotetralin Enantiomers and Positional Isomers

¹ Department of Pharmacology, University of Toronto, Toronto, CANADA M5S 1A8
² The Wellcome Research Laboratories, Burroughs Wellcome Co., 3030 Cornwallis Road, Research Triangle Park, N.C. 27709, U.S.A.

In order to test the identity of the [³H]-apomorphine receptor with the [³H]-dopamine receptor in brain, and to determine the conformation of dopamine at that receptor, we tested the binding affinities of some semi-rigid dopamine analogues. The enantiomers of 5-hydroxy-N,N-di-n-propyl-2-aminotetralin, a semi-rigid analogue of dopamine in the -rotamer conformation, showed stereospecific binding to the [³H]-dopamine, [³H]-apomorphine and [³H]-spiperone receptors in crude homogenate of calf-brain striatum. The affinity of the -rotamer analogue of dopamine, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin, to these receptors was from 5 to 22 times weaker. Substitution of the hydroxyl into the 6-position, analogous to p-tyramine, resulted in the lowest affinity for these receptors. The results are consistent with the identity of the [³H]-apomorphine with the [³H]-dopamine receptor. The identity of the dopamine agonist receptor with the antagonist receptor, however, remains controversial. Thus, the probable absolute conformation of dopamine at this agonist receptor is defined in terms of the torsion angles of the ethylamine side-chain of the dopamine moiety in R-(-)-apomorphine, with the nitrogen lone electron pair orientation at the agonist receptor also defined.

Note:
ACKNOWLEDGMENTS We thank Mrs. Joan Dumas and Mrs. Anna Banaschuk for excellent assistance. We also thank Drs. J. L. Neumeyer, J. P. Long and B. Costall for the kind gifts, respectively, of R-(-)-N-n-propylnorapomorphine, N,N-di-n-propyl-dopamine and m-tyramine.

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